Immunomodulatory_Roles_of_Statin/Ezetimibe

[Title of corresponding article] Distinct Effects of Rosuvastatin and Rosuvastatin/Ezetimibe on Senescence Markers of CD8+ T cells in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Trial [Author list] Sang-Hyeon Ju1†, Thi Linh Nguyen2†, Joung Youl Lim1, Minchul Song1, Ji Min Kim3,4, Yea Eun Kang1,4, Hyon-Seung Yi1,2,4, Kyong Hye Joung3,4, Ju Hee Lee1,4, Hyun Jin Kim1,4, Bon Jeong Ku1,4* 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Republic of Korea 2Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea 3Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Republic of Korea 4Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea. †; equal contribution for co-first author *; corresponding author [Abstract] Objectives Chronic low-grade inflammation has been widely recognized as a pathophysiological defect contributing to β-cell failure in type 2 diabetes mellitus (T2DM). Statin therapy is known to ameliorate CD8+ T cell senescence, a mediator of chronic inflammation. Additional immunomodulatory roles of ezetimibe are not fully understood. Therefore, we investigated the effect of statin or statin/ezetimibe combination treatment on T cell senescence markers. Methods In this two-group parallel and randomized controlled trial, we enrolled 149 patients with T2DM whose low-density lipoprotein cholesterol (LDL-C) was 100 mg/dL or higher. Patients were randomly assigned into rosuvastatin (N=74) or rosuvastatin/ezetimibe group (N=75). Immunophenotype of peripheral blood mononuclear cells and metabolic profiles were analyzed using samples of baseline and post-12 weeks of medication. Results Fractions of CD8+CD57+ (senescent CD8+ T cells) and CD4+FoxP3+ (Tregs) significantly decreased after intervention in the rosuvastatin/ezetimibe group (−4.5 ± 14.1 and −1.2 ± 2.3 %, respectively), while these fractions showed minimal change in the rosuvastatin group (2.8 ± 9.4 and 1.4 ± 1.5 %, respectively). The degree of LDL-C reduction was correlated with an improvement in HbA1c (R=0.193, p=0.021). Changes in the CD8+CD57+ fraction positively correlated with patient age (R=0.538, p=0.026). Notably, fraction change in senescent CD8+ T cells showed no significant relationship with changes in either HbA1c (p=0.314) or LDL-C (p=0.592). Finally, the ratio of naïve to memory CD8+ T cells increased in the rosuvastatin/ezetimibe group (p=0.011), but not in the rosuvastatin group (p=0.339). Conclusions We observed a reduction in senescent CD8+ T cells and an increase in the ratio of naive to memory CD8+ T cells by rosuvastatin/ezetimibe treatment. Our results demonstrate the immunomodulatory roles of ezetimibe in combination with statins, which are independent of improvements in lipid or HbA1c levels.【对应文章标题】 瑞舒伐他汀与瑞舒伐他汀/依折麦布对2型糖尿病(Type 2 Diabetes Mellitus, T2DM)患者CD8+ T细胞(CD8+ T cells)衰老标志物的不同影响：一项随机对照试验 【作者列表】 朱相铉1†, 阮氏灵2†, 林正烈1, 宋敏哲1, 金智敏3,4, 姜艺恩1,4, 尹铉承1,2,4, 郑庆惠3,4, 李珠熙1,4, 金贤镇1,4, 具奉正1,4* 1韩国大田忠南大学医院内科内分泌与代谢科 2韩国大田忠南大学医学院医学系 3韩国世宗忠南大学世宗医院内科内分泌与代谢科 4韩国大田忠南大学医学院内科 †：共同第一作者贡献相同 *：通讯作者 【摘要】 ■研究目标 慢性低度炎症已被广泛认为是导致2型糖尿病(T2DM)β细胞衰竭的病理生理缺陷。已知他汀类药物治疗可改善CD8+ T细胞衰老——一种慢性炎症的介导因子。依折麦布的额外免疫调节作用尚未完全阐明。因此，本研究旨在探讨他汀类药物或他汀类/依折麦布联合治疗对T细胞衰老标志物的影响。 ■研究方法 本研究为两组平行设计的随机对照试验，共纳入149例低密度脂蛋白胆固醇(Low-Density Lipoprotein Cholesterol, LDL-C)≥100 mg/dL的2型糖尿病患者。患者被随机分配至瑞舒伐他汀组(N=74)或瑞舒伐他汀/依折麦布联合组(N=75)。分别采集基线及服药12周后的样本，分析外周血单个核细胞的免疫表型与代谢特征。 ■研究结果 瑞舒伐他汀/依折麦布组干预后，CD8+CD57+（衰老CD8+ T细胞）及CD4+FoxP3+（调节性T细胞(Tregs)）占比显著降低[分别为(-4.5 ± 14.1)%和(-1.2 ± 2.3)%]；而瑞舒伐他汀组上述细胞占比仅出现轻微变化[分别为(2.8 ± 9.4)%和(1.4 ± 1.5)%]。低密度脂蛋白胆固醇(LDL-C)的降低幅度与糖化血红蛋白(HbA1c)的改善呈正相关(R=0.193, P=0.021)。CD8+CD57+占比的变化与患者年龄呈正相关(R=0.538, P=0.026)。值得注意的是，衰老CD8+ T细胞占比的变化与糖化血红蛋白(HbA1c)变化(P=0.314)或低密度脂蛋白胆固醇(LDL-C)变化(P=0.592)均无显著相关性。最后，瑞舒伐他汀/依折麦布组的初始型/记忆型CD8+ T细胞比值升高(P=0.011)，而瑞舒伐他汀组未出现明显变化(P=0.339)。 ■研究结论 本研究观察到，瑞舒伐他汀/依折麦布联合治疗可降低衰老CD8+ T细胞占比，并升高初始型/记忆型CD8+ T细胞比值。本研究结果证实，依折麦布与他汀类药物联合具有免疫调节作用，且该作用独立于血脂或糖化血红蛋白(HbA1c)水平的改善。